Abstract
Purpose
The p42.3 gene is identified recently, and the upregulated expression has been characterized in a variety of human cancers and embryonic tissues but not yet in malignant melanoma. In this study, we explored the role of p42.3 gene in the development of melanoma.
Methods
The expression of p42.3 was detected by immunohistochemistry staining of 261 cases of patient lesions, including nevi and melanoma, and its correlation with clinical pathological characteristics and prognosis was analyzed. Furthermore, a series of in vitro assays were used to investigate the biological function of p42.3 in melanoma cells.
Results
Immunohistochemistry staining showed an elevated expression level of p42.3 in melanoma compared to nevi (P = 0.001). Statistical analysis indicated that this high level was well correlated with patients’ clinical stage (P = 0.045), but not with gender, age, clinical type, mitotic rate, and overall survival (P > 0.05). Moreover, in vitro assays showed knockdown p42.3 gene expression could inhibit the biological profiling, including proliferation, migration, and invasion of melanoma cells, and also affect PI3K/Akt pathway, MAPK pathway, and β-catenin.
Conclusions
This study suggests that p42.3, acting like an oncogene, is involved in the malignant transformation process of melanoma and may serve as a biomarker for diagnostic and treatment purposes.
Similar content being viewed by others
References
Bastian BC (2014) The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia. Annu Rev Pathol 9:239–271. doi:10.1146/annurev-pathol-012513-104658
Bertolotto C (2013) Melanoma: from melanocyte to genetic alterations and clinical options. Scientifica (Cairo) 2013:635203 doi:10.1155/2013/635203
Chan PM, Ilangumaran S, La Rose J, Chakrabartty A, Rottapel R (2003) Autoinhibition of the kit receptor tyrosine kinase by the cytosolic juxtamembrane region. Mol Cell Biol 23:3067–3078
Chapman PB et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516. doi:10.1056/NEJMoa1103782
Chi Z, Li S, Sheng X, Si L, Cui C, Han M, Guo J (2011) Clinical presentation, histology, and prognoses of malignant melanoma in ethnic Chinese: a study of 522 consecutive cases. BMC Cancer 11:85. doi:10.1186/1471-2407-11-85
Clark WH Jr, Elder DE, Guerry Dt, Epstein MN, Greene MH, Van Horn M (1984) A study of tumor progression: the precursor lesions of superficial spreading and nodular melanoma. Hum Pathol 15:1147–1165
Cully M, You H, Levine AJ, Mak TW (2006) Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 6:184–192. doi:10.1038/nrc1819
Dossett LA, Kudchadkar RR, Zager JS (2015) BRAF and MEK inhibition in melanoma. Expert Opin Drug Saf 14:559–570. doi:10.1517/14740338.2015.1011618
Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606–619. doi:10.1038/nrg1879
Flaherty KT et al (2012) Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367:107–114. doi:10.1056/NEJMoa1203421
Hao Y, Fan T, Nan K (2015) Optimization and corroboration of the regulatory pathway of p42.3 protein in the pathogenesis of gastric carcinoma. Comput Math Methods Med 2015:683679. doi:10.1155/2015/683679
Johnson DB et al (2015) Impact of NRAS mutations for patients with advanced melanoma treated with immune therapies cancer. Immunol Res 3:288–295. doi:10.1158/2326-6066.CIR-14-0207
Li PH, Cao WJ, Mao LL, Huang H, Zheng JN, Pei DS (2014) p42.3 promotes cell proliferation and invasion in human Renal-Cell Carcinoma. Int J Clin Exp Med 7:4959–4966
Liu H et al (2013) A DNA vaccine targeting p42.3 induces protective antitumor immunity via eliciting cytotoxic CD8 + T lymphocytes in a murine melanoma model. Hum Vaccin Immunother 9:2196–2202. doi:10.4161/hv.25013
Mao L, Sun W, Li W, Cui J, Zhang J, Xing R, Lu Y (2014) Cell cycle-dependent expression of p42.3 promotes mitotic progression in malignant transformed cells. Mol Carcinog 53:337–348. doi:10.1002/mc.21982
McDermott D, Haanen J, Chen TT, Lorigan P, O’Day S, Investigators MDX (2013) Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol 24:2694–2698. doi:10.1093/annonc/mdt291
Miller AJ, Mihm MC Jr (2006) Melanoma. N Engl J Med 355:51–65. doi:10.1056/NEJMra052166
Omholt K, Platz A, Kanter L, Ringborg U, Hansson J (2003) NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res 9:6483–6488
Oyama S, Funasaka Y, Watanabe A, Takizawa T, Kawana S, Saeki H (2015) BRAF, KIT and NRAS mutations and expression of c-KIT, phosphorylated extracellular signal-regulated kinase and phosphorylated AKT in Japanese melanoma patients. J Dermatol 42:477–484. doi:10.1111/1346-8138.12822
Rimm DL, Caca K, Hu G, Harrison FB, Fearon ER (1999) Frequent nuclear/cytoplasmic localization of beta-catenin without exon 3 mutations in malignant melanoma. Am J Pathol 154:325–329
Robert C et al (2014) Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 384:1109–1117. doi:10.1016/S0140-6736(14)60958-2
Robert C et al (2015) Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 372:2521–2532. doi:10.1056/NEJMoa1503093
Roider EM, Fisher DE (2014) The impact of MITF on melanoma development: news from bench and bedside. J Invest Dermatol 134:16–17. doi:10.1038/jid.2013.390
Sosman JA et al (2012) Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366:707–714. doi:10.1056/NEJMoa1112302
Sun W, Dong WW, Mao LL, Li WM, Cui JT, Xing R, Lu YY (2013) Overexpression of p42.3 promotes cell growth and tumorigenicity in hepatocellular carcinoma. World J Gastroenterol 19:2913–2920. doi:10.3748/wjg.v19.i19.2913
Tumeh PC et al (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568–571. doi:10.1038/nature13954
Weber JS et al (2015) Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16:375–384
Weng YR et al (2014) Role of C9orf140 in the promotion of colorectal cancer progression and mechanisms of its upregulation via activation of STAT5, beta-catenin and EZH2. Carcinogenesis 35:1389–1398. doi:10.1093/carcin/bgu057
Wu H, Goel V, Haluska FG (2003) PTEN signaling pathways in melanoma. Oncogene 22:3113–3122. doi:10.1038/sj.onc.1206451
Xu X et al (2007) Identification and characterization of a novel p42.3 gene as tumor-specific and mitosis phase-dependent expression in gastric cancer. Oncogene 26:7371–7379. doi:10.1038/sj.onc.1210538
Yuan XS et al (2013) p42.3: a promising biomarker for the progression and prognosis of human colorectal cancer. J Cancer Res Clin Oncol 139:1211–1220. doi:10.1007/s00432-013-1434-0
Yuzawa S, Opatowsky Y, Zhang Z, Mandiyan V, Lax I, Schlessinger J (2007) Structural basis for activation of the receptor tyrosine kinase KIT by stem cell factor. Cell 130:323–334. doi:10.1016/j.cell.2007.05.055
Acknowledgements
This work was supported by grants from Beijing Nova Program (No. 2010B033), Beijing Municipal Science and Technology Commission Capital Characteristic Clinical Application Research (No. Z141107002514077), and Beijing Medical Discipline Backbone Program (No. 2010-3-088) by Beijing Municipal Health Bureau.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Rights and permissions
About this article
Cite this article
Liu, H., Zhu, M., Li, Z. et al. Depletion of p42.3 gene inhibits proliferation and invasion in melanoma cells. J Cancer Res Clin Oncol 143, 639–648 (2017). https://doi.org/10.1007/s00432-016-2328-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-016-2328-8